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Functional molecular switches of mammalian G protein-coupled bitter-taste receptors

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Abstract

Bitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs). The experimental structure of these receptors has yet to be determined, and key-residues controlling their function remain mostly unknown. We designed an integrative approach to improve comparative modeling of TAS2Rs. Using current knowledge on class A GPCRs and existing experimental data in the literature as constraints, we pinpointed conserved motifs to entirely re-align the amino-acid sequences of TAS2Rs. We constructed accurate homology models of human TAS2Rs. As a test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis and in vitro functional assays. This combination of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular switches that encode agonist sensing and downstream signaling mechanisms within mammalian TAS2Rs sequences.

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Fig. 1
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taken from PDB code 5JQH

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Code and data availability

The scripts used to generate and analyze the models as well as PDB files of TAS2Rs 3D models with the highest meta-score have been deposited on GitHub. (https://github.com/chemosim-lab/TAS2R_data).

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Acknowledgements

The authors thank Dr. Xiaojing Cong for fruitful discussion and critical review of the manuscript. This work was funded by the French Ministry of Higher Education and Research [PhD Fellowship to CB], by the National Research Foundation of Korea (NRF) [grant number NRF2020R1A2C2004661], by GIRACT (Geneva, Switzerland) [9th European PhD in Flavor Research Bursaries for first year students to CB], and the Gen Foundation (Registered UK Charity No. 1071026), a charitable trust that primarily funds research in natural sciences, particularly food sciences/technology [grant to CB and JT]. We also benefited from funding by the French government through the UCAJEDI “Investments in the Future” project, managed by the ANR [grant No. ANR-15-IDEX-01 to SF and JG]. Computation for the work described in this paper was supported by the Université Côte d’Azur’s Center for High-Performance Computing.

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  1. Jérémie Topin and Cédric Bouysset are co-first authors.

Authors and Affiliations

  1. Institut de Chimie de Nice UMR7272, Université Côte d’Azur, CNRS, Nice, France

    Jérémie Topin, Cédric Bouysset, Jody Pacalon, Sébastien Fiorucci & Jérôme Golebiowski

  2. Korea Food Research Institute, 245 Iseo-myeon, Wanju-gun, Jeollabuk-do, 55365, Republic of Korea

    Yiseul Kim & Mee-Ra Rhyu

  3. Department of Brain and Cognitive Sciences, DGIST, 333, Techno JungAng, Daero, HyeongPoong Myeon, Daegu, 711-873, Republic of Korea

    Jérôme Golebiowski

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Contributions

JT†, CB†, and JP performed numerical modeling. YK and MR conducted functional assays. JT, CB, and SF performed data curation. JT, CB, JP, YK, and MR conducted formal analyses. JT, SF, and JG supervised and managed the study and wrote the paper. MR and JG provided resources for this study.

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Correspondence to Jérémie Topin or Sébastien Fiorucci.

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Topin, J., Bouysset, C., Pacalon, J. et al. Functional molecular switches of mammalian G protein-coupled bitter-taste receptors. Cell. Mol. Life Sci. 78, 7605–7615 (2021). https://doi.org/10.1007/s00018-021-03968-7

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